Fertőző betegségek Szervátültetés Tumorok eliminálása

1. THE ROLE OF PROFESSIONAL ANTIGEN PRESENTING CELLS IN THE IMMUNE RESPONSE Fertőző betegségek Szervátültetés Tumorok eliminálása Gatekeeper funkció Kórokozók „érzékelése” Adaptív immunválasz elindítása Saját struktúrákkal szembeni tolerancia fenntartása

2. PROFESSIONAL ANTIGEN PRESENTING CELLS Express MHC class I and class II molecules Express co-stimulatory molecules (B7, CD40) Take up extracellular antigens B cells – soluble proteins, toxins (ADAPTIVE) Macrophages – extracellular pathogens (bacteria, yeast) INNATE – particles Dendritic cells – viruses, apoptotic cells

3. PROFESSIONAL ANTIGEN PRESENTING CELLS Express MHC class I and class II molecules Express co-stimulatory molecules (CD40, B7) Take up extracellular antigens B cells – soluble proteins, toxins ADAPTIVE – Ag specific Macrophages – extracellular pathogens (bacteria, yeast) Dendritic cells – viruses, apoptotic cells INNATE ~25% 3 – 6% ~1%

4. CHARACTERISTICS OF PROFESSIONAL ANTIGEN PRESENTING CELLS Macrophage Dendritic cell B - lymphocyte Ag uptake phagocytosis +++ phagocytosis +++ Ag-specific mIg virus infection ++++ ++++ MHC expression induced +/+++ constitutive ++++constitutive +++ bacteria, cytokine immature/mature +++/++++ activation ++++ Pesented Ag particulate Ag protein soluble protein intra/extracellular virus protein, allergen toxin pathogens apoptotic cell Co-stimulation induced +/++ constitutive ++++induced +/+++ éretlen/érett+++/++++ Localization lymphoid tissue lymphoid tissue lymphoid tissue connective tissue connective tissue peripheral blood body cavities epithelium Lymph node evenly immature –tissue follicles mature –T cell area

5. CO-STIMULATION IS ESSENTIAL FOR PRIMING OF NAIVE T LYMPHOCYTES The antigen-specific and the co-stimulatory signal has to be induced in concert to induce T lymphocyte activation The antigen-specific and co-stimulatory signals can be delivered simultaneously by professional antigen presenting cells, only The antigen-specific and the co-stimulatory singnals has to be delivered by the same professional antigen presenting cell

7. ORIGIN AND DIFFERENTIATION OF HUMAN DENDRITIC CELLS CD34+HPC BONE MARROW MYELOID LYMPHOID CMP CLP CD34+ CLA+ CD34+ CLA- BLOOD Pre-Tα Vλ5 CD14+ CD11c+ CD1a+ CD11c+ CD1a- IPC/preDC2 Monocyte/preDC1 DC1/myeloid Macrophage Interstitial DC2/plasmacytoid Langerhans/LC TISSUE

8. CHANGES OF TISSUE ENVIRONMENT INDUCES THE ACTIVATION OF MACROPHAGES AND DENDRITIC CELLS Phagocytosis and degradation of backteria (LPS, TLR) DANGER SIGNAL Macrophage Activated macrophage Monocyte Dendritic cell Activated dendritic cell Virus, extracellular pathogens, inflammatory cytokines (LPS, TLR) DANGER SIGNAL BLOOD TISSUE LYMPHOID TISSUE

9. Effector and memory T cells Lymphatics Activated DC Inflammation Pathogen Naive T cells ANTIGEN CIRCULATION Tissue DC ACTIVATION AND MIGRATION OF DENDRITIC CELLS TISSUE LYMPH NODE TISSUE DC AND T CELLS ENCOUNTER T CELL ACTIVATION

10. Dendritic cells are sensors gatekeepers and messengers Activation induce a phenotype essential for initiation of the adaptive immune response

11. INTERDIGITATING RETICULAR (MATURE DENDRITIC) CELL IN T CELL AREAS OF LYMPH NODES NUCLEUS T CELL T CELL CYTOPLASM

12. Cell-surface molecules of the immunoglobulin superfamily initiate lymphocyte adhesion to professional antigen-presenting cells. B. Transient interactions are stabilized by Ag-binding A. Initial contact A

13. Capture of an Ag-Specific T Cell by an Ag-Bearing DC Rapid DC Migration in the Subcapsular Space Bone-marrow derived DCs (either 5 µM CFSE, green) or (50 µM Cell Tracker Blue, blue) were injected into the footpad of a C57BL/6 mouse, followed 18 hours later by intravenous injection of freshly isolated polyclonal CD4+ T cells (5 µM SNARF, red) and CD8+ T cells (5 µM CFSE and 5 µM SNARF, yellow). The draining LN was removed 6 hours after injection Bone-marrow derived DCs (yellow) were pulsed with 1 µM Ova 4 peptide and 10 µM Ova for 1 hour at 37oC, then injected into the footpad of a C57BL/6 recipient. This was followed 6 hours later by i.v. co-injection of OT-I CD8+ T cells (5 µM CFSE, green) and OT-II CD4+ T cells (5 µM SNARF, red). Huang et al Immunity 2004

14. CONTACT OF DENDRITIC CELLS AND T - LYMPHOCYTES IN LYMPHOID ORGANS Activated dendritic cells act as professional antigen presenting cells MHC-peptide complexes 1. signal STRANGER Co-stimulatory molecule 2. signal AMPLIFICATION Cytokines 3. signal DANGER They are in close contact with specific T lymphocytes

15. HUMAN MYELOID DENDRITIC CELLS MDC DC1/DC2 LYMPHOID ORGANS DC – T interaction Cognate Th/Tc activation Th1/Th2 instruction ACTIVATION IDC TISSUE Mobility Antigen processing & presentation MHCI/MHCII Antigen uptake Activation

16. Morphology of plasmacytoid dendritic cells IPC/DC2 pDC monocyte Scanning EM Transmission EM

17. Plasmacytoid DCs control the function of many immunocytes IFNα is impotant in SLE pathology HIV infects PDC Role in immune response and in the pathogenesis of autoimmune diseases and cancer

18. PLASMACYTOID DENDRITIC CELLS AS PROFESSIONAL TYPE I INTERFERON SECRETING CELLS Enhanced NK cell cytotoxic activity TLR4 Vírus infection TRAM TRIF TLR7 TLR8 TLR9 TLR3 TRIF MyD88 TANK IRAK-1 Activation of  and γδ T cells TRAF-6 RIG-1 IKKε TBK1 IFN-β IFN-α1 Cross-presentation by conventional dendritic cells is enhanced IRF-3 IRF-5 IRF-7 IRF-7 Ig production by B cells is induced Type I interferon receptor

19. Migration Pathways of PDC/IPC versus mDC into a lymph node mDC: afferent lymphatics IPC: HEV Both migrate into the T-cell rich areas

20. ONE, TWO and DANGER signal hypothesis Self- nonself models Matzinger, P. Science, 296. 301- (2002)

21. No danger Cell containing only self antigens APC No danger Apoptotic cell death. A natural, often useful cell death. APC The danger hypothesis & co-stimulation Full expression of T cell function and self tolerance depends upon when and where co-stimulatory molecules are expressed. Innocuous challenge to the immune system fails to activate APC and fails to activate the immune system Fuchs & Matzinger 1995

22. Necrotic cell death e.g. tissue damage, virus infection etc APC APC DANGER Pathogens recognised by microbial patterns The danger hypothesis APC that detect ‘danger’ signals express costimulatory molecules, activate T cells and the immune response

23. Some implications of the danger hypothesis • There is no window for tolerance induction in neonates • Neonatal T cells are not intrinsically tolerant but the neonatal environment predisposes to tolerance • Antigens induce tolerance or immunity depending upon the ability of the immune system to sense them as ‘dangererous’, and not by sensing whether they are self or ‘non-self’. • Apoptosis, the ‘non-dangerous’ death of self cells may prevent autoimmunity when old or surplus cells are disposed of. • Suggests that tolerance is the default pathway of the immune system on encountering antigens. • Explains why immunisations require adjuvants to stimulate cues of danger such as cytokines or costimulatory molecule expression. Doesn’t exclude self-nonself discrimination, but is very hard to enequivocally disprove experimentally

24. PROFESSIONAL ANTIGEN PRESENTING CELLS